Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain
Cindy Wen, Michael Margolis, Rujia Dai, Pan Zhang, Pawel F. Przytycki, Daniel Vo, Arjun Bhattacharya, Nana Matoba, Miao Tang, Chuan Jiao, Minsoo Kim, Ellen Tsai, Celine Hoh, Nil Aygün, Rebecca L. Walker, Christos Chatzinakos, Declan Clarke, Henry Pratt, Mette A. Peters, Mark Gerstein, Nikolaos P. Daskalakis, Zhiping Weng, Andrew E. Jaffe, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger, Nicholas J. Bray, Nenad Šestan, Daniel H. Geschwind, Kathryn Roeder, Alexander Gusev, Bogdan Paşaniuc, Jason L. Stein, Michael I. Love, Katherine S. Pollard, Chunyu Liu, Michael J. Gandal, Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul Bharadwaj, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A. Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen, H. Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew Chess, Jo-fan Chien, Zhiyuan Chu, Ashley Clement, Leonardo Collado‐Torres, Gregory M. Cooper, Gregory E. Crawford, José Dávila-Velderrain, Amy Deep‐Soboslay, Chengyu Deng, Christopher P. DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc M. Duong, Cagatay Dursun, Nicholas J. Eagles, Jonathan I. Edelstein, Prashant S. Emani, John F. Fullard, Kiki Galani, Timur R. Galeev, Sophia C. Gaynor, Kiran Girdhar, Fernando S. Goes, William J. Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He, Ella Henry, Stephanie C. Hicks, Marcus Ho, Li‐Lun Ho, Gabriel E. Hoffman, Yi‐Ling Huang, Louise A. Huuki-Myers, Ahyeon Hwang
Abstract
Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.